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Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

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Immunobiology: The Immune System in Health and Disease. 5th edition.

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Acquired immune deficiency syndrome

The first cases of the acquired immune deficiency syndrome (AIDS) were reported in 1981 but it is now clear that cases of the disease had been occurring unrecognized for at least 4 years before its identification. The disease is characterized by a susceptibility to infection with opportunistic pathogens or by the occurrence of an aggressive form of Kaposi's sarcoma or B-cell lymphoma, accompanied by a profound decrease in the number of CD4 T cells. As it seemed to be spread by contact with body fluids, it was early suspected to be caused by a new virus, and by 1983 the agent now known to be responsible for AIDS, called the human immunodeficiency virus (HIV), was isolated and identified. It is now clear there are at least two types of HIV—HIV-1 and HIV-2—which are closely related to each other. HIV-2 is endemic in West Africa and is now spreading in India. Most AIDS worldwide, however, is caused by the more virulent HIV-1. Both viruses appear to have spread to humans from other primate species and the best evidence from sequence relationships suggests that HIV-1 has passed to humans on at least three independent occasions from the chimpanzee, Pan troglodytes, and HIV-2 from the sooty mangabey, Cercocebus atys.

HIV infection does not immediately cause AIDS, and the issues of how it does, and whether all HIV-infected patients will progress to overt disease, remain controversial. Nevertheless, accumulating evidence clearly implicates the growth of the virus in CD4 T cells, and the immune response to it, as the central keys to the puzzle of AIDS. HIV is a worldwide pandemic and, although great strides are being made in understanding the pathogenesis and epidemiology of the disease, the number of infected people around the world continues to grow at an alarming rate, presaging the death of many people from AIDS for many years to come. Estimates from the World Health Organization are that 16.3 million people have died from AIDS since the beginning of the epidemic and that there are currently around 34.3 million people alive with HIV infection (Fig. 11.19), of whom the majority are living in sub-Saharan Africa, where approximately 7% of young adults are infected. In some countries within this region, such as Zimbabwe and Botswana, over 25% of adults are infected. (Image clinical_small.jpgAIDS in Mother and Child, in Case Studies in Immunology, see Preface for details)

Figure 11.19. HIV infection is spreading on all continents.

Figure 11.19

HIV infection is spreading on all continents. The number of HIV-infected individuals is large (data are numbers of adults and children living with HIV/AIDS at the end of 1999, as estimated by the World Health Organization) and is increasing rapidly, especially (more...)

11-17. Most individuals infected with HIV progress over time to AIDS

Many viruses cause an acute but limited infection inducing lasting protective immunity. Others, such as herpes viruses, set up a latent infection that is not eliminated but is controlled adequately by an adaptive immune response. However, infection with HIV seems rarely, if ever, to lead to an immune response that can prevent ongoing replication of the virus. Although the initial acute infection does seem to be controlled by the immune system, HIV continues to replicate and infect new cells.

The initial infection with HIV generally occurs after transfer of body fluids from an infected person to an uninfected one. The virus is carried in infected CD4 T cells, dendritic cells, and macrophages, and as a free virus in blood, semen, vaginal fluid, or milk. It is most commonly spread by sexual intercourse, contaminated needles used for intravenous drug delivery, and the therapeutic use of infected blood or blood products, although this last route of transmission has largely been eliminated in the developed world where blood products are screened routinely for the presence of HIV. An important route of virus transmission is from an infected mother to her baby at birth or through breast milk. In Africa, the perinatal transmission rate is approximately 25%, but this can largely be prevented by treating infected pregnant women with the drug zidovudine (AZT) (see Section 11-23). Mothers who are newly infected and breastfeed their infants transmit HIV 40% of the time, showing that HIV can also be transmitted in breast milk, but this is less common after the mother produces antibodies to HIV. (Image clinical_small.jpgAIDS in Mother and Child, in Case Studies in Immunology, see Preface for details)

Primary infection with HIV is probably asymptomatic in 50% of cases but often causes an influenza-like illness with an abundance of virus in the peripheral blood and a marked drop in the numbers of circulating CD4 T cells. This acute viremia is associated in virtually all patients with the activation of CD8 T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The cytotoxic T-cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4 T-cell counts rebound to around 800 cells μl-1 (the normal value is 1200 cells μl-1). At present, the best indicator of future disease is the level of virus that persists in the blood plasma once the symptoms of acute viremia have passed.

Most patients who are infected with HIV will eventually develop AIDS, after a period of apparent quiescence of the disease known as clinical latency or the asymptomatic period (Fig. 11.20). This period is not silent, however, for there is persistent replication of the virus, and a gradual decline in the function and numbers of CD4 T cells until eventually patients have few CD4 T cells left. At this point, which can occur anywhere between 2 and 15 years or more after the primary infection, the period of clinical latency ends and opportunistic infections begin to appear.

Figure 11.20. Most HIV-infected individuals progress to AIDS over a period of years.

Figure 11.20

Most HIV-infected individuals progress to AIDS over a period of years. The incidence of AIDS increases progressively with time after infection. Homosexuals and hemophiliacs are two of the groups at highest risk in the West—homosexuals from sexually (more...)

The typical course of an infection with HIV is illustrated in Fig. 11.21. However, it has become increasingly clear that the course of the disease can vary widely. Thus, although most people infected with HIV go on to develop AIDS and ultimately to die of opportunistic infection or cancer, this is not true of all individuals. A small percentage of people seroconvert, making antibodies against many HIV proteins, but do not seem to have progressive disease, in that their CD4 T-cell counts and other measures of immune competence are maintained. These long-term nonprogressors have unusually low levels of circulating virus and are being studied intensively to determine how they are able to control their HIV infection. A second group consists of seronegative people who have been highly exposed to HIV yet remain disease-free and virus-negative. Some of these people have specific cytotoxic lymphocytes and TH1 lymphocytes directed against infected cells, which confirms that they have been exposed to HIV or possibly noninfectious HIV antigens. It is not clear whether this immune response accounts for clearing the infection, but it is a focus of considerable interest for the development and design of vaccines, which we will discuss later. There is a small group of people who are resistant to HIV infection because they carry mutations in a cell-surface receptor that is used as a co-receptor for viral entry, as we will see below.

Figure 11.21. The typical course of untreated infection with HIV.

Figure 11.21

The typical course of untreated infection with HIV. The first few weeks are typified by an acute influenza-like viral illness, sometimes called seroconversion disease, with high titers of virus in the blood. An adaptive immune response follows, which controls (more...)

We will return to discuss in more detail the interactions of HIV with the immune system and the prospects for manipulating them later in this chapter, but before doing so we must describe the viral life cycle and the genes and proteins on which it depends. Some of these proteins are the targets of the most successful drugs in use at present for the treatment of AIDS.

11-18. HIV is a retrovirus that infects CD4 T cells, dendritic cells, and macrophages

HIV is an enveloped retrovirus whose structure is shown in Fig. 11.22. Each virus particle, or virion, contains two copies of an RNA genome, which are transcribed into DNA in the infected cell and integrated into the host cell chromosome. The RNA transcripts produced from the integrated viral DNA serve both as mRNA to direct the synthesis of the viral proteins and later as the RNA genomes of new viral particles, which escape from the cell by budding from the plasma membrane, each in a membrane envelope. HIV belongs to a group of retroviruses called the lentiviruses, from the Latin lentus, meaning slow, because of the gradual course of the diseases that they cause. These viruses persist and continue to replicate for many years before causing overt signs of disease.

Figure 11.22. The virion of human immunodeficiency virus (HIV).

Figure 11.22

The virion of human immunodeficiency virus (HIV). The virus illustrated is HIV-1, the leading cause of AIDS. The reverse transcriptase, integrase, and viral protease enzymes are packaged in the virion and are shown schematically in the viral capsid. In (more...)

The ability of HIV to enter particular types of cell, known as the cellular tropism of the virus, is determined by the expression of specific receptors for the virus on the surface of those cells. HIV enters cells by means of a complex of two noncovalently associated viral glycoproteins, gp120 and gp41, in the viral envelope. The gp120 portion of the glycoprotein complex binds with high affinity to the cell-surface molecule CD4. This glycoprotein thereby draws the virus to CD4 T cells and to dendritic cells and macrophages, which also express some CD4. Before fusion and entry of the virus, gp120 must also bind to a co-receptor in the membrane of the host cell. Several different molecules may serve as a co-receptor for HIV entry, but in each case they have been identified as chemokine receptors. The chemokine receptors (see Chapters 2 and 10) are a closely related family of G protein-coupled receptors with seven transmembrane-spanning domains. Two chemokine receptors, known as CCR5, which is predominantly expressed on dendritic cells, macrophages, and CD4 T cells, and CXCR4, expressed on activated T cells, are the major co-receptors for HIV. After binding of gp120 to the receptor and co-receptor, the gp41 then causes fusion of the viral envelope and the plasma membrane of the cell, allowing the viral genome and associated viral proteins to enter the cytoplasm.

There are different variants of HIV, and the cell types that they infect are determined to a large degree by which chemokine receptor they bind as co-receptor. The variants of HIV that are associated with primary infections use CCR5, which binds the CC chemokines RANTES, MIP-1α, and MIP-1β (see Chapter 2), as a co-receptor, and require only a low level of CD4 on the cells they infect. These variants of HIV infect dendritic cells, macrophages, and T cells in vivo. However, they are often described simply as ‘macrophage-tropic’ because they infect macrophage but not T-cell lines in vitro and the cell tropism of different HIV variants was originally defined by their ability to grow in different cell lines.

In contrast, ‘lymphocyte-tropic’ variants of HIV infect only CD4 T cells in vivo and use CXCR4, which binds the CXC chemokine stromal-derived factor-1 (SDF-1), as a co-receptor. The lymphocyte-tropic variants of HIV can grow in vitro in T-cell lines, and require high levels of CD4 on the cells that they infect.

It appears that macrophage-tropic isolates of HIV are preferentially transmitted by sexual contact as they are the dominant viral phenotype found in newly infected individuals. Virus is disseminated from an initial reservoir of infected dendritic cells and macrophages and there is evidence for an important role for mucosal lymphoid tissue in this process. Mucosal epithelia, which are constantly exposed to foreign antigens, provide a milieu of immune system activity in which HIV replication occurs readily. Infection of CD4 T cells via CCR5 occurs early in the course of infection and continues to occur, with activated CD4 T cells accounting for the major production of HIV throughout infection. Late in infection, in approximately 50% of cases, the viral phenotype switches to a T-lymphocyte-tropic type that utilizes CXCR4 co-receptors, and this is followed by a rapid decline in CD4 T-cell count and progression to AIDS.

11-19. Genetic deficiency of the macrophage chemokine co-receptor for HIV confers resistance to HIV infection in vivo

Further evidence for the importance of chemokine receptors in HIV infection has come from studies in a small group of individuals with high-risk exposure to HIV-1 but who remain seronegative. Cultures of lymphocytes and macrophages from these people were relatively resistant to macrophage-tropic HIV infection and were found to secrete high levels of RANTES, MIP-1α and MIP-1β in response to inoculation with HIV. In other experiments, the addition of these same chemokines to lymphocytes sensitive to HIV blocked their infection because of competition between these CC chemokines and the virus for the cell-surface receptor CCR5.

The resistance of these rare individuals to HIV infection has now been explained by the discovery that they are homozygous for an allelic, nonfunctional variant of CCR5 caused by a 32-base-pair deletion from the coding region that leads to a frameshift and truncation of the translated protein. The gene frequency of this mutant allele in Caucasoid populations is quite high at 0.09 (meaning that about 10% of the Caucasoid population are heterozygous carriers of the allele and about 1% are homozygous). The mutant allele has not been found in Japanese or black Africans from Western or Central Africa. Heterozygous deficiency of CCR5 might provide some protection against sexual transmission of HIV infection and a modest reduction in the rate of progression of the disease. In addition to the structural polymorphism of the gene, variation of the promoter region of the CCR5 gene has been found in both Caucasian and African Americans. Different promoter variants were associated with different rates of progression of disease.

These results provide a dramatic confirmation of experimental work suggesting that CCR5 is the major macrophage and T-lymphocyte co-receptor used by HIV to establish primary infection in vivo, and offers the possibility that primary infection might be blocked by therapeutic antagonists of the CCR5 receptor. Indeed, there is preliminary evidence that low molecular weight inhibitors of this receptor can block infection of macrophages by HIV in vitro. Such low molecular weight inhibitors might be the precursors of useful drugs that could be taken by mouth. Such drugs are very unlikely to provide complete protection against infection, as a very small number of individuals who are homozygous for the nonfunctional variant of CCR5 are infected with HIV. These individuals seem to have suffered from primary infection by CXCR4-using strains of the virus.

11-20. HIV RNA is transcribed by viral reverse transcriptase into DNA that integrates into the host cell genome

One of the proteins that enters the cell with the viral genome is the viral reverse transcriptase, which transcribes the viral RNA into a complementary DNA (cDNA) copy. The viral cDNA is then integrated into the host cell genome by the viral integrase, which also enters the cell with the viral RNA. The integrated cDNA copy is known as the provirus. The infectious cycle up to the integration of the provirus is shown in Fig. 11.23. In activated CD4 T cells, virus replication is initiated by transcription of the provirus, as we will see in the next section. However, HIV can, like other retroviruses, establish a latent infection in which the provirus remains quiescent. This seems to occur in memory CD4 T cells and in dormant macrophages, and these cells are thought to be an important reservoir of infection.

Figure 11.23. The infection of CD4 T cells by HIV.

Figure 11.23

The infection of CD4 T cells by HIV. The virus binds to CD4 using gp120, which is altered by CD4 binding so that it now also binds a specific seven-span chemokine receptor that acts as a co-receptor for viral entry. This binding releases gp41, which then (more...)

The entire HIV genome consists of nine genes flanked by long terminal repeat sequences (LTRs), which are required for the integration of the provirus into the host cell DNA and contain binding sites for gene regulatory proteins that control the expression of the viral genes. Like other retroviruses, HIV has three major genes—gag, pol, and env. The gag gene encodes the structural proteins of the viral core, pol encodes the enzymes involved in viral replication and integration, and env encodes the viral envelope glycoproteins. The gag and pol mRNAs are translated to give polyproteins—long polypeptide chains that are then cleaved by the viral protease (also encoded by pol) into individual functional proteins. The product of the env gene, gp160, has to be cleaved by a host cell protease into gp120 and gp41, which are then assembled as trimers into the viral envelope. As shown in Fig. 11.24, HIV has six other, smaller, genes encoding proteins that affect viral replication and infectivity in various ways. We will discuss the function of two of these—Tat and Rev—in the following section.

Figure 11.24. The genes and proteins of HIV-1.

Figure 11.24

The genes and proteins of HIV-1. Like all retroviruses, HIV-1 has an RNA genome flanked by long terminal repeats (LTR) involved in viral integration and in regulation of the viral genome. The genome can be read in three frames and several of the viral (more...)

11-21. Transcription of the HIV provirus depends on host cell transcription factors induced upon the activation of infected T cells

The production of infectious virus particles from an integrated HIV provirus is stimulated by a cellular transcription factor that is present in all activated T cells. Activation of CD4 T cells induces the transcription factor NFκB, which binds to promoters not only in the cellular DNA but also in the viral LTR, thereby initiating the transcription of viral RNA by the cellular RNA polymerase. This transcript is spliced in various ways to produce mRNAs for the viral proteins. The Gag and Gag-Pol proteins are translated from unspliced mRNA; Vif, Vpr, Vpu, and Env are translated from singly spliced viral mRNA; Tat, Rev, and Nef are translated from multiply spliced mRNA. At least two of the viral genes, tat and rev, encode proteins, Tat and Rev respectively, that promote viral replication in activated T cells. Tat is a potent transcriptional regulator, which functions as an elongation factor that enables the transcription of viral RNA by the RNA polymerase II complex. Tat contains two binding sites, contained in one domain, named the transactivation domain. The first of these allows Tat to bind to a host cellular protein, cyclin T1. This binding reaction promotes the binding of the Tat protein through the second binding site in its transactivation domain to an RNA sequence in the LTR of the virus known as the transcriptional activation region (TAR). The consequence of this interaction is to greatly enhance the rate of viral genome transcription, by causing the removal of negative elongation factors that block the transcriptional activity of RNA polymerase II. The expression of cyclin T1 is greatly increased in activated compared with quiescent T lymphocytes. This, in conjunction with the increased expression of NFκB in activated T cells, may explain the ability of HIV to lie dormant in resting T cells and replicate in activated T cells (Fig. 11.25).

Figure 11.25. Cells infected with HIV must be activated for the virus to replicate.

Figure 11.25

Cells infected with HIV must be activated for the virus to replicate. Activation of CD4 T cells induces the expression of the transcription factor NFκB, which binds to the proviral LTR and initiates the transcription of the HIV genome into RNA. (more...)

Eukaryotic cells have mechanisms to prevent the export from the cell nucleus of incompletely spliced mRNA transcripts. This could pose a problem for a retrovirus that is dependent on the export of unspliced, singly spliced, and multiply spliced mRNA species in order to translate the full complement of viral proteins. The Rev protein is the viral solution to this problem. Export from the nucleus and translation of the three HIV proteins encoded by the fully spliced mRNA transcripts, Tat, Nef, and Rev, occurs early after viral infection by means of the normal host cellular mechanisms of mRNA export. The expressed Rev protein then enters the nucleus and binds to a specific viral RNA sequence, the Rev response element (RRE). Rev also binds to a host nucleocytoplasmic transport protein named Crm1, which engages a host pathway for exporting mRNA species through nuclear pores into the cytoplasm.

When the provirus is first activated, Rev levels are low, the transcripts are translocated slowly from the nucleus, and thus multiple splicing events can occur. Thus, more Tat and Rev are produced, and Tat in turn ensures that more viral transcripts are made. Later, when Rev levels have increased, the transcripts are translocated rapidly from the nucleus unspliced or only singly spliced. These unspliced or singly spliced transcripts are translated to produce the structural components of the viral core and envelope, together with the reverse transcriptase, the integrase, and the viral protease, all of which are needed to make new viral particles. The complete, unspliced transcripts that are exported from the nucleus late in the infectious cycle are required for the translation of gag and pol and are also destined to be packaged with the proteins as the RNA genomes of the new virus particles.

11-22. Drugs that block HIV replication lead to a rapid decrease in titer of infectious virus and an increase in CD4 T cells

Studies with powerful drugs that completely block the cycle of HIV replication indicate that the virus is replicating rapidly at all phases of infection, including the asymptomatic phase. Two viral proteins in particular have been the target of drugs aimed at arresting viral replication. These are the viral reverse transcriptase, which is required for synthesis of the provirus, and the viral protease, which cleaves the viral polyproteins to produce the virion proteins and viral enzymes. Inhibitors of these enzymes prevent the establishment of further infection in uninfected cells. Cells that are already infected can continue to produce virions because, once the provirus is established, reverse transcriptase is not needed to make new virus particles, while the viral protease acts at a very late maturation step of the virus, and inhibition of the protease does not prevent virus from being released. However, in both cases, the released virions are not infectious and further cycles of infection and replication are prevented.

Because of the great efficacy of the protease inhibitors, it is possible to learn much about the kinetics of HIV replication in vivo by measuring the decline in viremia after the initiation of protease inhibitor therapy. For the first 2 weeks after starting treatment there is an exponential fall in plasma virus levels with a half-life of viral decay of about 2 days (Fig. 11.26). This phase reflects the decay in virus production from cells that were actively infected at the start of drug treatment, and indicates that the half-life of productively infected cells is similarly about 2 days. The results also show that free virus is cleared from the circulation very rapidly, with a half-life of about 6 hours. After 2 weeks, levels of virus in plasma have dropped by more than 95%, representing an almost total loss of productively infected CD4 lymphocytes. After this time, the rate of decline of plasma virus levels is much slower, reflecting the very slow decay of virus production from cells that provide a longer-lived reservoir of infection, such as dendritic cells and tissue macrophages, and from latently infected memory CD4 T cells that have been activated. Very long-term sources of infection might be CD4 memory T cells that continue to carry integrated provirus, and virus stored as immune complexes on follicular dendritic cells. These very long-lasting reservoirs of infection might prove to be resistant to drug therapy for HIV.

Figure 11.26. Viral decay on drug treatment.

Figure 11.26

Viral decay on drug treatment. The production of new HIV virus particles can be arrested for prolonged periods by combinations of protease inhibitors and viral reverse transcriptase inhibitors. After the initiation of such treatment, the virus produced (more...)

These studies show that most of the HIV present in the circulation of an infected individual is the product of rounds of replication in newly infected cells, and that virus from these productively infected cells is released into, and rapidly cleared from, the circulation at the rate of 109 to 1010 virions every day. This raises the question of what is happening to these virus particles: how are they removed so rapidly from the circulation? It seems most likely that HIV particles are opsonized by specific antibody and complement and removed by phagocytic cells of the mononuclear phagocyte system. Opsonized HIV particles can also be trapped on the surface of follicular dendritic cells, which are known to capture antigen:antibody complexes and retain them for prolonged periods (see Chapters 9 and 10).

The other issue raised by these studies is the effect of HIV replication on the population dynamics of CD4 T cells. The decline in plasma viremia is accompanied by a steady increase in CD4 T lymphocyte counts in peripheral blood: what is the source of the new CD4 T cells that appear once treatment is started? It seems highly unlikely that they are the recent progeny of stem cells that have developed in the thymus, because CD4 T cells are not normally produced in large numbers from the thymus even at its maximum rate of production in adolescents. Some investigators believe that these cells are emerging from sites of sequestration and add little to the total numbers of CD4 T cells in the body, whereas others advocate their origin from mature CD4 T cells that replicate, and argue that the production of such cells is an ongoing process that compensates for the continual loss of productively infected CD4 T cells.

11-23. HIV accumulates many mutations in the course of infection in a single individual and drug treatment is soon followed by the outgrowth of drug-resistant variants of the virus

The rapid replication of HIV, with the generation of 109 to 1010 virions every day, coupled with a mutation rate of approximately 3 × 10-5 per nucleotide base per cycle of replication, leads to the generation of many variants of HIV in a single infected patient in the course of one day. Replication of a retroviral genome depends on two error-prone steps. Reverse transcriptase lacks the proofreading mechanisms associated with cellular DNA polymerases, and the RNA genomes of retroviruses are therefore copied into DNA with relatively low fidelity; the transcription of the proviral DNA into RNA copies by the cellular RNA polymerase is similarly a low-fidelity process. A rapidly replicating persistent virus that is going through these two steps repeatedly in the course of an infection can thereby accumulate many mutations, and numerous variants of HIV, sometimes called quasi-species, are found within a single infected individual. This very high variability was first recognized in HIV and has since proved to be common to the other lentiviruses.

As a consequence of its high variability, HIV rapidly develops resistance to antiviral drugs. When antiviral drugs are administered, variants of the virus that carry mutations conferring resistance to their effects emerge and expand until former levels of plasma virus are regained. Resistance to some of the protease inhibitors appears after only a few days (Fig. 11.27). Resistance to some of the nucleoside analogues that are potent inhibitors of reverse transcriptase develops in a similarly short time. By contrast, resistance to the nucleoside zidovudine (AZT), the first drug to be widely used for treating AIDS, takes months to develop. This is not because AZT is a more powerful inhibitor, but because resistance to zidovudine requires three or four mutations in the viral reverse transcriptase, whereas a single mutation can confer resistance to the protease inhibitors and other reverse-transcriptase inhibitors. As a result of the relatively rapid appearance of resistance to all known anti-HIV drugs, successful drug treatment might depend on the development of a range of antiviral drugs that can be used in combination. It might also be important to treat early in the course of an infection, thereby reducing the chances that a variant virus has accumulated all the necessary mutations to resist the entire cocktail. Current treatments follow this strategy and use combinations of viral protease inhibitors together with nucleoside analogues (see Fig. 11.26).

Figure 11.27. Resistance of HIV to protease inhibitors.

Figure 11.27

Resistance of HIV to protease inhibitors. After the administration of a single protease inhibitor to a patient with HIV there is a precipitous fall in viral RNA levels in plasma with a half-life of approximately 2 days (top panel). This is accompanied (more...)

11-24. Lymphoid tissue is the major reservoir of HIV infection

Although viral load and turnover are usually measured by detecting the viral RNA present in viral particles in the blood, the major reservoir of HIV infection is in lymphoid tissue, in which infected CD4 T cells, monocytes, macrophages, and dendritic cells are found. In addition, HIV is trapped in the form of immune complexes on the surface of follicular dendritic cells. These cells are not themselves infected but may act as a store of infective virions.

HIV infection takes different forms within different cells. As we have seen, more than 95% of the virus that can be detected in the plasma is derived from productively infected cells, which have a very short half-life of about 2 days. Productively infected CD4 lymphocytes are found in the T-cell areas of lymphoid tissue, and these are thought to succumb to infection in the course of being activated in an immune response. Latently infected memory CD4 cells that are activated in response to antigen presentation also produce virus. Such cells have a longer half-life of 2 to 3 weeks from the time that they are infected. Once activated, HIV can spread from these cells by rounds of replication in other activated CD4 T cells. In addition to the cells that are infected productively or latently, there is a further large population of cells infected by defective proviruses; such cells are not a source of infectious virus.

Macrophages and dendritic cells seem to be able to harbor replicating virus without necessarily being killed by it, and are therefore believed to be an important reservoir of infection, as well as a means of spreading virus to other tissues such as the brain. Although the function of macrophages as antigen-presenting cells does not seem to be compromised by HIV infection, it is thought that the virus causes abnormal patterns of cytokine secretion that could account for the wasting that commonly occurs in AIDS patients late in their disease.

11-25. An immune response controls but does not eliminate HIV

Infection with HIV generates an adaptive immune response that contains the virus but only very rarely, if ever, eliminates it. The time course of various elements in the adaptive immune response to HIV is shown, together with the levels of infectious virus in plasma, in Fig. 11.28.

Figure 11.28. The immune response to HIV.

Figure 11.28

The immune response to HIV. Infectious virus is present at relatively low levels in the peripheral blood of infected individuals during a prolonged asymptomatic phase, during which the virus is replicated persistently in lymphoid tissues. During this (more...)

Seroconversion is the clearest evidence for an adaptive immune response to infection with HIV, but the generation of T lymphocytes responding to infected cells is thought by most workers in the field to be central in controlling the infection. Both CD8 cytotoxic T cells and TH1 cells specifically responsive to infected cells are associated with the decline in detectable virus after the initial infection. These T-cell responses are unable to clear the infection completely and can cause some pathology. Nevertheless, there is evidence that the virus itself is cytopathic, and T-cell responses that reduce viral spread should therefore, on balance, reduce the pathology of the disease.

The ability of cytotoxic T lymphocytes to destroy HIV-infected cells is demonstrated by studies of peripheral blood cells from infected individuals, in which cytotoxic T cells specific for viral peptides can be shown to kill infected cells in vitro. In vivo, cytotoxic T cells can be seen to invade sites of HIV replication and they could, in theory, be responsible for killing many productively infected cells before any infectious virus can be released, thereby containing viral load at the quasi-stable levels that are characteristic of the asymptomatic period. The best evidence for the clinical importance of the control of HIV-infected cells by CD8 cytotoxic T cells comes from studies relating the numbers and activity of CD8 T cells to viral load. An inverse correlation was found between the number of CD8 T cells carrying a receptor specific for an HLA-A2-restricted HIV peptide and plasma RNA viral load. Similarly, patients with high levels of HIV-specific CD8 T cells showed slower progression of disease than those with low levels. There is also direct evidence from experiments in macaques infected with simian immunodeficiency virus (SIV) that CD8 cytotoxic T cells control retrovirally-infected cells in vivo. Treatment of infected animals with depleting anti-CD8 monoclonal antibodies was followed by a large increase in viral load.

Mutations that occur as HIV replicates can allow variants of the virus to escape recognition by antibody or cytotoxic T cells and can contribute to the failure of the immune system to contain the infection in the long term. Direct escape of virus-infected cells from killing by cytotoxic T lymphocytes has been shown by the occurrence of mutations of immunodominant viral peptides presented by MHC class I molecules. In other cases, variant peptides produced by the virus have been found to act as antagonists (see Section 6-12) for T cells responsive to the wild-type epitope, thus allowing both mutant and wild-type viruses to survive. Mutant peptides acting as antagonists have also been reported in hepatitis B virus infections, and similar mutant peptides might contribute to the persistence of some viral infections, especially when, as often happens, the immune response of an individual is dominated by T cells specific for a particular epitope.

11-26. HIV infection leads to low levels of CD4 T cells, increased susceptibility to opportunistic infection, and eventually to death

There are three dominant mechanisms for the loss of CD4 T cells in HIV infection. First, there is evidence for direct viral killing of infected cells; second, there is increased susceptibility to the induction of apoptosis in infected cells; and third, there is killing of infected CD4 T cells by CD8 cytotoxic lymphocytes that recognize viral peptides.

When CD4 T-cell numbers decline below a critical level, cell-mediated immunity is lost, and infections with a variety of opportunistic microbes appear (Fig. 11.29). Typically, resistance is lost early to oral Candida species and to Mycobacterium tuberculosis, which shows as an increased prevalence of thrush (oral candidiasis) and tuberculosis. Later, patients suffer from shingles, caused by the activation of latent herpes zoster, from EBV-induced B-cell lymphomas, and from Kaposi's sarcoma, a tumor of endothelial cells that probably represents a response both to cytokines produced in the infection and to a novel herpes virus called HHV-8 that was identified in these lesions. Pneumonia caused by the fungus Pneumocystis carinii is common and often fatal. In the final stages of AIDS, infection with cytomegalovirus or Mycobacterium avium complex is more prominent. It is important to note that not all patients with AIDS get all these infections or tumors, and there are other tumors and infections that are less prominent but still significant. Rather, this is a list of the commonest opportunistic infections and tumors, most of which are normally controlled by robust CD4 T cell-mediated immunity that wanes as the CD4 T-cell counts drop toward zero (see Fig. 11.21).

Figure 11.29. A variety of opportunistic pathogens and cancers can kill AIDS patients.

Figure 11.29

A variety of opportunistic pathogens and cancers can kill AIDS patients. Infections are the major cause of death in AIDS, with respiratory infection with Pneumocystis carinii and mycobacteria being the most prominent. Most of these pathogens require effective (more...)

11-27. Vaccination against HIV is an attractive solution but poses many difficulties

A safe and effective vaccine for the prevention of HIV infection and AIDS is an attractive goal, but its achievement is fraught with difficulties that have not been faced in developing vaccines against other diseases. The first problem is the nature of the infection itself, featuring a virus that proliferates extremely rapidly and causes sustained infection in the face of strong cytotoxic T-cell and antibody responses. As we discussed in Section 11-25, HIV evolves in individual patients by the selective proliferative advantage of mutant virions encoding peptide sequence changes that escape recognition by antibodies and by cytotoxic T lymphocytes. This evolution means that the development of therapeutic vaccination strategies to block the development of AIDS in HIV-infected patients will be extremely difficult. Even after the viremia has been largely cleared by drug therapy, immune responses to HIV fail to prevent drug-resistant virus from rebounding and replicating at pretreatment levels.

The second problem is our uncertainty over what form protective immunity to HIV might take. It is not known whether antibodies, cytotoxic T lymphocyte responses, or both are necessary to achieve protective immunity, and which epitopes might provide the targets of protective immunity. Third, if strong cytotoxic responses are necessary to provide protection against HIV, these might be difficult to develop and sustain through vaccination. Other effective viral vaccines rely on the use of live, attenuated viruses and there are concerns over the safety of pursuing this approach for HIV. Another possible approach is the use of DNA vaccination, a technique that we discuss in Section 14-25. Both of these approaches are being tested in animal models.

The fourth problem is the ability of the virus to persist in latent form as a transcriptionally silent provirus, which is invisible to the immune system. This might prevent the immune system from clearing the infection once it has been established. In summary, the ability of the immune system to clear infectious virus remains uncertain.

However, against this pessimistic background, there are grounds for hope that successful vaccines can be developed. Of particular interest are rare groups of people who have been exposed often enough to HIV to make it virtually certain that they should have become infected but who have not developed the disease. In some cases this is due to an inherited deficiency in the chemokine receptor used as co-receptor for HIV entry, as we explained in Section 11-19. However, this mutant chemokine receptor does not occur in Africa, where one such group has been identified. A small group of Gambian and Kenyan prostitutes who are estimated to have been exposed to many HIV-infected male partners each month for up to 5 years were found to lack antibody responses but to have cytotoxic T lymphocyte responses to a variety of peptide epitopes from HIV. These women seem to have been naturally immunized against HIV.

Although there is no perfect animal model for the development of HIV vaccines, one model system is based on simian immunodeficiency virus (SIV), which is closely related to HIV and infects macaques. SIV causes a similar disease to AIDS in Asian macaques such as the cynomolgus monkey, but does not cause disease in African cercopithecus monkeys such as the African green monkey, with which SIV has probably coexisted for up to a million years. Live attenuated SIV vaccines lacking the nef gene, and hybrid HIV-SIV viruses have been developed to test the principles of vaccination in primates, and both have proved successful in protecting primates against subsequent infection by fully virulent viruses. However, there are substantial difficulties to be overcome in the development of live attenuated HIV vaccines for use in at-risk populations, not least the worry of recombination between vaccine strains and wild-type viruses leading to reversion to a virulent phenotype. The alternative approach of DNA vaccination is being piloted in primate experiments, with some early signs of success.

Subunit vaccines, which induce immunity to only some proteins in the virus, have also been made. One such vaccine has been made from the envelope protein gp120 and has been tested on chimpanzees. This vaccine proved to be specific to the precise strain of virus used to make it, and was therefore useless in protection against natural infection. Subunit vaccines are also less efficient at inducing prolonged cytotoxic T-cell responses.

Finally, there are difficult ethical issues in the development of a vaccine. It would be unethical to conduct a vaccine trial without trying at the same time to minimize the exposure of a vaccinated population to the virus itself. However, the effectiveness of a vaccine can only be assessed in a population in which the exposure rate to the virus is high enough to assess whether vaccination is protective against infection. This means that initial vaccine trials might have to be conducted in countries where the incidence of infection is very high and public health measures have not yet succeeded in reducing the spread of HIV.

11-28. Prevention and education are one way in which the spread of HIV and AIDS can be controlled

The one way in which we know we can protect against infection with HIV is by avoiding contact with body fluids, such as semen, blood, blood products, or milk from people who are infected. Indeed, it has been demonstrated repeatedly that this precaution, simple enough in the developed world, is sufficient to prevent infection, as health-care workers can take care of AIDS patients for long periods without seroconversion or signs of infection.

For this strategy to work, however, one must be able to test people at risk of infection with HIV periodically, so that they can take the steps necessary to avoid passing the virus to others. This, in turn, requires strict confidentiality and mutual trust. A barrier to the control of HIV is the reluctance of individuals to find out whether they are infected, especially as one of the consequences of a positive HIV test is stigmatization by society. As a result, infected individuals can unwittingly infect many others. Balanced against this is the success of therapy with combinations of the new protease inhibitors and reverse transcriptase inhibitors, which provides an incentive for potentially infected people to identify the presence of infection and gain the benefits of treatment. Responsibility is at the heart of AIDS prevention, and a law guaranteeing the rights of people infected with HIV might go a long way to encouraging responsible behavior. The rights of HIV-infected people are protected in the Netherlands and Sweden. The problem in the less-developed nations, where elementary health precautions are extremely difficult to establish, is more profound.

Summary

Infection with the human immunodeficiency virus (HIV) is the cause of acquired immune deficiency syndrome (AIDS). This worldwide epidemic is now spreading at an alarming rate, especially through heterosexual contact in less-developed countries. HIV is an enveloped retrovirus that replicates in cells of the immune system. Viral entry requires the presence of CD4 and a particular chemokine receptor, and the viral cycle is dependent on transcription factors found in activated T cells. Infection with HIV causes a loss of CD4 T cells and an acute viremia that rapidly subsides as cytotoxic T-cell responses develop, but HIV infection is not eliminated by this immune response. HIV establishes a state of persistent infection in which the virus is continually replicating in newly infected cells. The current treatment consists of combinations of viral protease inhibitors together with nucleoside analogues and causes a rapid decrease in virus levels and a slower increase in CD4 T-cell counts. The main effect of HIV infection is the destruction of CD4 T cells, which occurs through the direct cytopathic effects of HIV infection and through killing by CD8 cytotoxic T cells. As the CD4 T-cell counts wane, the body becomes progressively more susceptible to opportunistic infection with intracellular microbes. Eventually, most HIV-infected individuals develop AIDS and die; however a small minority (3–7%), remain healthy for many years, with no apparent ill effects of infection. We hope to be able to learn from these individuals how infection with HIV can be controlled. The existence of such people and other people who have been naturally immunized against infection gives hope that it will be possible to develop effective vaccines against HIV.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2001, Garland Science.
Bookshelf ID: NBK27126

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